Preparation of the metal salts of acetylsalicylic acid



Patented Mar. 12, 1935 c 1 UNITED STATES, PATENT OFFICE PREPARATION OF THE METAL SALTS OF ACETYLSALICYLIC ACID Clemmy 0. Miller, Chicago, 11].

No Drawing. Application April 15, 1933, Serial No. 666,327

14 Claims. (Cl. 260-107) g,

This invention relates to the preparation of cium acetylsalicylate, free from calcium salimetal salts of acetylsalicylic acid, and more parcylate, salicylic acid, and acetylsalicylic acid, ticularly to a process whereby these salts are predoes not produce these toxic side actions. For pared free from salicylates, salicylic acid, and example, high calcium acetylsalicylate medicaacetylsalicylic acid. tion, free from calcium'salicylate, salicylic acid, 5 In one embodiment, the present invention is and acetylsalicylic acid is possible in cases of directed particularly to the preparation of calarthritis andrheumatic fever without the. apcium acetylsalicylate free from calcium salicylate, pearance of toxic side reactions, In cases of salicylic acid, and acetylsalicylic acid. However, patients intolerant towards acetylsalicylic' acid 10. the invention is not'limited to the production of and salicylates, I have found that they can tolcalcium acetylsalicylate, since, in its broad erate my calcium acetylsalicylate without diffiaspects, the invention embraces the production culty and receive-relief. Furthermore, in animals of all metal salts of acetylsalicylic acid. given massive does of calcium acetylsalicylat'e,

Acetylsalicylic acid is widely used as an analfree from calcium salicylate, salicylic acid, and

15 gesic and antipyretic in cases of headache, neuacetylsalicylic acid, histologic sections of liver, 1,5

ralgias, coldsyfevers, arthritis, rheumatic fever, kidney and gastric mucosa show no pathological et cetera: salicylates, as sodium salicylate, are lesions under conditions which give pathological used in rheumatic fever, rheumatic tonsilitis, lesions when the animals are given acetylsalicylic and fevers. Concerning the therapeutic adminacid and salicylates.

v istration of acetylsalicylic acid, salicylic acid, I have found that the methods which are now 20 and salicylates, Sollman in his Manual of in use for the production of calcium acetylsali- Pharmacology, Third Edition, 1926, Saunders, cylate do not give products free from salicylate I pp. 613-614, and 619, states, ,For internal use, and stable towards storage and ordinary ha'n-, the free salicylic acid is too irritant. When the dling, the decomposition during storage and dosage of salicylate'is raised to the full thera handling being such that free salicylic acid and 25 peutic effect, there occursusually a series of side calcium sa1icylate are formed. I have developed actions resembling cinchonism. They consist of a process whereby calcium acetylsalicylate can, nausea and vomiting, ringing in the ears-and be prepared free from calcium salicylate, salicylic deafness, vertigo and headache, mental dullness acid and acetylsalicylic acid and in a condition 30. and confusion, diaphoresis, quickening pulse, and which does not decompose during storage and deepened respiration, rarely skin eruptions, albuordinary handling to give these compounds, minuria, impaired vision and delirium, the latter The present inventionresides in carrying out especially in alcoholic patients. To be efiecthe reaction whereby calc m cetyl'salicylate is tive in acute rheumatism, large doses mustbe formed in a 50111171011 having, & DH Within t administered: 1 to 1.3 gm. should be givenevery range of 2 .to 7 (two to seven), and preferably hour until toxic symptoms (tinnitus, nausea, Wit n the range of 4 to '7 (four to seven), and et cetera) set in. The administration should bringing the reactants together in such a way- 7 then be stopped for twelve hours. Referring to, that the reaction takes place y qu c y, With the benefits fromsalicylate medication, he states, precipitation 0f l tp 40 These benefits last only so long as the patient The followingis an illustrative example utiliz- 40 is kept salicylated and relapses occur when this ing the invention in the preparation of calcium' is discontinued. Salicylates may have a slight acetylsalicylate: Fifty-two parts of anhydrous and inconstant diuretic effect. Full'doses, hows calcium acetate may be dissolved in 200 parts of ever, decrease the output of urine, partly by water containing two parts of glacial acetic acid.

diaphoresis, partly by water retention This is Seventy-two parts of acetylsalicylic acid may be 45 accompanied by evidences of renal irritation dissolved in 200 parts of methanol. The solution (slight albuminand casts) and diminished renal of acetylsalicylic acid is slowly added to the solupermeability (phthalein test and non-protein tion of calcium acetate with stirring, during a penitrogen of blood) Highly toxic doses produce riod of two to thirty minutes. Calcium acetylsal 0 anatomic parenchymatous lesions. Concerning icylate separates as a fine white precipitate. The acetylsalicylic acid medication, he states, It precipitate is separated from the mother liquor produces some gastric irritation. Acetylsaliby any convenient process, such as filtration, cencylic acid is about one and one-half as toxic as trifuging, et cetera, and may be washed with ether sodium salicylate in man. v 1 l or a small amount of methanol to remove any 5 I have'found that the administration of cal-. unchanged acetylsalicylic acid. The precip tate can be dried by exposure to warm air at atmospheric pressure or at reduced. pressure or by any other convenient process.

Acetylsalicylic acid, being in part an ester, is progressively saponified in solutions having a pH greater than '7, giving a salicylate, which has undesirable pharmacological properties, as-hereinbefore pointed out. In prior processes for preparing calcium acetylsalicylate, acetylsalicylic acid is exposed to a basic solution for several hours. This accounts, in part, for the presence of salicylate in the products.

I have found that the decomposition of acetylsalicylic acid into salicylic acid takes place much more slowly at a pH below '7 than it does when the pH is above 7. A Water solution of calcium acetate is slightly alkaline, so I prefer to make it slightly acid with acetic acid before combining it with acetylsalicylic acid. While the reaction can be carried out without the addition of acetic acid to the calcium acetate before combining with acetylsalicylic acid, I prefer to never expose acetylsalicylic acid to a solution having a pH greater than 7, even for a short period of time. During the reaction between calcium acetate and acetylsalicylic acid, acetic acid is formed, the concentration of which increases as the reaction proceeds. By using an excess of calcium acetate, the ionization of the newly formed acetic acid is depressed due to the effect of the common ion. The pH of the solution is approximately 5. I can control the pH of the solution by using the requiredexcess of the acetate. Any calcium salicylate that is formed, and any acetylsalicylic acid that has not reacted, remains in the mother liquor.

My invention as it relates to the production of calcium acetylsalicylate is not limited to the use of any specific proportion of calcium acetate, acetic acid, and acetylsalicylic acid, since the use of other proportions leads also to the formation of calcium acetylsalicylate. Neither is my invention limited to the use of any specific proportions of solvent or solvents, since other propbrtions give similar results. While I'prefer to use Water as a solvent for calcium acetate and methanol as a solvent for acetylsalicylic acid, followed by their combination, Water alone and methanol alone may be used. Also I have found that other organic solvents or combinations of organic solvents that will dissolve acetylsalicylic acid and are miscible with water, as ethanol and ether, acetone, methyl acetate, et cetera, can be used instead of methanol. My invention is not limited to any solvent or system of solvents. Also other water soluble calcium salts may be used instead of calcium acetate, provided precautions are taken to carryout the reaction in the pH range of 2 to 7. The essential feature of my invention is that the reaction is carried out in a solution having a pH within the range of .2 to '7.

I have further found that when calcium acetylsalicylate is precipitated rapidly, that a small amount of calcium acetate is carried down with it. The presence of this substance in the calcium acetylsalicylate renders it more stable towards storage and ordinary handling.

While I have described my invention as it relates to the preparation of calcium acetylsalicylate, free from calcium salicylate, salicylic acid, and acetylsalicylic acid, it is not to be construed that it is limited to the preparation only of calcium acetylsalicylate, as it is applicable to the preparation of all of the metal salts of acetylsalicylic acid. The term metalsalts of acetylsalicylic acid, includes the monovalent metal salts, lithium, sodium, and potassium acetylsalicylates; the bivalent metal salts, magnesium, calcium, and strontium acetylsalicylates; and the trivalent metal salts, aluminum and bismuth acetylsalicylates.

Some acids in addition to acetic acid whose Water solutions have pI-Is in the range of 2 to '7, are citric, salicylic, benzoic, formic, butyric, lactic and succinic. When any of these is used in conjunction with its metal salts, the pH of the solution is maintained near the pK value of the acid because of the effect of the common ion.

I claim as my invention:

1. A process for preparing the metal salts of acetylsalicylic acid free from salicylic acid and acetylsalicylic acid, which comprises adjusting the pH value of a solution of a metal salt selected from the group consisting of the monovalent, bivalent and trivalent soluble metal salts of carboxylic acids to below 7 and above 2, combining the solution of the selected metal salt adjustedto said pH value range with acetylsalicylic acid;

maintaining said resulting solution at a .pH value within the range of 2 to 7, and recovering the precipitate.

2. A process for preparing the metal salts of acetylsalicylic acid free from salicylic acid and acetylsalicylic acid, which comprises adjusting the pH value of a solution of a metal salt selected from the group consisting of the moncvalent, bivalent and trivalent soluble metal salts of carboxylic acids to below 7 and above 2, combining the solution of the selected metal salt adjusted to said pH value range with acetylsalicylic acid in a solution of an organic solvent miscible with water, maintaining said resulting solution at a pH value within the range of 2 to '7, and recovering the precipitate. 1

3. A process for preparing the metal salts of acetylsalicylic acid free from salicylic acid and acetylsalicylic acid, which comprises adjusting the pH value of a solution of a metal salt selected from the group consisting of the monovalent, bivalent and trivalent soluble metal salts of carboxylic acids to below land above 4, combining the solution of the selected metal salt adjusted to said pH value range with acetylsalicylic acid in a solution of an organic solvent miscible with water, maintaining said resulting solution at a pH value within the range of 4 to 7, and recovering the precipitate.

4. A process for'preparing calcium acetylsalicylate free from salicylic acid and acetylsalicylic acid, which comprises adjusting the pH value of a solution of calcium acetate to below 7 and above 4, combining said calcium acetate solution adjusted to said pH value range with acetylsalicylic acid, maintaining said resulting solution at a pH value within the range of 4 to '7, and recovering the precipitate.

5. A process for preparing calcium acetylsalicylate free from salicylic acid and acetylsalicylic acid, which comprises adjusting the pH value of a solution of a soluble calcium salt of carboxylic acids in Water to a pH value range between 2 and 7, combining said solution adjusted to said pH value range with acetylsalicylic acid dissolved in an organic solvent miscible with water, maintaining said resulting solution at a pH value within the range of 2 to '7, and recovering the precipitate.

6. A process for preparing calcium acetylsalicylate free from salicylic acid and acetylsalicylic acid, which comprises adjusting the pH value of a solution of a soluble metal salt of carboxylic acids in water to a pH value rangebetween 2 and 7, combining said solutio-nadjusted'to said pH value range with acetylsalicylic acid dissolved in an organic solvent miscible with Water, maintaining said resulting solution at a pH value within the range of 2 to 7, and recovering the precipitate.

7. A process for preparing calcium acetylsalicylate free from'salicylic acid and acetylsalicylic acid, which comprises combining calcium acetate with acetylsalicylic acid in a solution having a pH value within the range of 2 to '7, and recovering the precipitate.

8. A process for preparing the metal salts of acetylsalicylic acid free from salicylic acid and acetylsalicylic acid, which comprises combining a water-soluble metal salt selected from the group consisting of the monovalent, bivalent and tri-,

valent metal salts of carboxylic acids with acetylsalicylic acid in a solution containing acetic acid, and recovering the precipitate.

9. A process for preparing calcium acetylsalicylate free from salicylic acid and acetylsalicylic acid which comprises combining calcium acetate with acetylsalicylic acid in a solution containing acetic acid, and recovering the precipitate.

10. A process for preparing the metal salts of acetylsalicylic acid free from salicylic acid and acetylsalicylic acid, which comprises combining the acetate of a metal with acetylsalicylic acid.

in a solution containing acetic acid, and recovering the precipitate.

11. A process for preparing calcium acetylsalicylate free from salicylic acid and acetylsalicyllc *acid, which comprises combining a solution of from salicylic acid, metal salts of salicylic acidand from acetylsalicylic acid.

13. A new medicinal product consisting 01? calcium acetylsalicylate resulting from reacting a calcium salt of a carboxylic acid with acetylsalicylic acid while maintaining the pH value within the range of 2 to 7 during such reaction, and said product being substantially free from sali ,cylic acid, metal salts of salicylic acid andvfrom acetylsalicylic acid. 14. A new medicinal product consisting of calcium acetylsalicylateresulting from reacting calcium acetate with acetylsalicylic acid while maintaining the pH value within the range of 2 to? during such reaction, said product being sub stantially free from salicylic acid, metal salts of salicylic acid and from acetylsalicylic, acid, and containing a small amount of calcium acetate therein. 7 V

CLEMMY O. MILLER. 

